Abstract Heart failure with preserved ejection fraction (HFpEF) is a leading cause of mortality in the elderly. Outcomes of patients with HFpEF are poor and so far, no treatment has been shown to decrease morbidity or mortality. Recent animal and human studies suggest that a systemic proinflammatory state produced by comorbidities, including aging, plays a central role in the development of HFpEF, supporting the notion that attenuating the proinflammatory state is an attractive therapeutic target for HFpEF. We have previously shown that low-level transcutaneous electrical stimulation of the vagus nerve at the tragus (LLTS) suppresses inflammation in patients with atrial fibrillation. The overall objective of this proposal is to examine the effects of LLTS on diastolic dysfunction, exercise capacity and inflammation in patients with HFpEF and determine whether these effects are mediated by suppression of inflammation and fibrosis in a well-established rat model of HFpEF. Our specific aims include: 1. To examine the effect of intermittent (1 hour daily for 3 months) LLTS on diastolic dysfunction, exercise capacity and inflammation, relative to sham stimulation, in patients with HFpEF and 2. To determine the effect of intermittent (30 minutes daily for 4 weeks) LLTS on diastolic dysfunction, inflammation and fibrosis in a well-established HFpEF rat model. The proposed proof-of-concept human studies and mechanistic animal studies will provide the basis for the design of further human studies using LLTS among populations with HFpEF. In light of the increasing number of elderly patients with HFpEF, recognized as a key point of interest in this funding mechanism, and the poor success of the currently available treatment options, an alternative and novel approach such as LLTS has the potential to impact clinical practice and improve health outcomes among a large number of patients. It is anticipated that these investigations will contribute to the broader understanding of the role of inflammation in the pathogenesis of HFpEF and how its inhibition can be used to provide therapeutic effects. Moreover, it is anticipated that a better understanding of how modulation of inflammation affects one of the hallmarks of HFpEF, diastolic dysfunction, will lead to the development of novel pharmacological and non-pharmacological approaches to treat this disease.